Cyclosporin has been used as an immunosuppressant or antiinflammatory agent in organ transplants, for example, heart, lung, liver, kidney, pancreas, skin, cornea, and numerous other heterotransplants. In addition, it has been widely used for autoimmune diseases, for example, psoriasis gravis, Behcet's syndrome, Graves' disease, posterior uvetis, Crohn's disease, diabetes mellitus, ulcerative colitis, myasthenia gravis, rheumatoid arthritis, etc. Its efficacy in these has been reported.
In particular, efficacy by oral administration has been confirmed up to now for psoriasis. Many clinical test results have been reported at present (for example, British Journal of Dermatology, vol. 122, suppl. 36, 1990). In the case of oral administration, however, many side effects such so kidney toxicity, liver toxicity, specific to cyclosporin have been reported. Further, the bioavailability when orally administed is as low as about 30% and an amount of administration is difficult to determine due to the individual differences. Thus, there are many problems in treatment by oral administration.
In view of the above situations, methods of treatment involving direct application to the diseased part the psoriasis for transdermal absorption have been tried out and the development of an effective external agent free from the above side effects is desired. However, since cyclosporin is an active agent characterized by a large molecular weight and a high hydrophobicity, transdermal absorption of cyclosporin cannot be expected in the case of some preparations in which cyclosporin is dispersed in lyophilic bases such as white petrolatum and liquid paraffin or hydrophilic base such as polyethylene glycols.
Further, since cyclosporin dissolves well in methanol, ethanol, acetone, ether, chloroform, etc., external administration by a preparation in which cyclosporin is dissolved in an alcohol, particularly ethanol, has been considered. However, since crystals of cyclosporin easily precipitate after the alcohol evaporates, it is not possible to include the active ingredient at a high concentration and therefore it is not possible to ensure a sufficient amount for treatment be absorbed through the skin. Further, in the case of psoriasis or atopic dermatitis requiring long term continuous use, an alcohol-containing preparation cannot necessarily be said to be preferable when considering skin safety.
As prior art relating to cyclosporin-containing compositions, emulsion preparations containing medium chain fatty acid diglycerides or monoglycerides are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-49733, emulsion compositions containing hydrophilic components, medium chain fatty acid triglycerides, and surfactants are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-121929, pharmaceutical compositions composed of fatty acid saccharide monoesters and diluents are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-235817, pharmaceutical compositions composed of fatty acid triglycerides, partical fatty acid glycerides, etc. are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-255623, and emulsion compositions containing medium chain fatty acid triglycerides, vegetable oils, surfactants, etc. are disclosed in Japanese Unexamined Patent Publication (Kokai) No. 2-290809.
However, even with these prior arts, since it was impossible to formulate the cyclosporin at a high concentration and, also since, the stability of the preparations was insufficient, these have not been yet commercialized.